RESUMO
BACKGROUND AND OBJECTIVES: Primary spinal glioblastoma (PsGBM) is extremely rare. The dramatic neurologic deterioration and unresectability of PsGBM makes it a particularly disabling malignant neoplasm. Because it is a rare and heterogeneous disease, the assessment of prognostic factors remains limited. METHODS: PsGBMs were identified from the French Brain Tumor Database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie retrospectively. Inclusion criteria were age 18 years or older at diagnosis, spinal location, histopathologic diagnosis of newly glioblastoma according to the 2016 World Health Organization classification, and surgical management between 2004 and 2016. Diagnosis was confirmed by a centralized neuropathologic review. The primary outcome was overall survival (OS). Therapeutic interventions and neurologic outcomes were also collected. RESULTS: Thirty-three patients with a histopathologically confirmed PsGBM (median age 50.9 years) were included (27 centers). The median OS was 13.1 months (range 2.5-23.7), and the median progression-free survival was 5.9 months (range 1.6-10.2). In multivariable analyses using Cox model, Eastern Cooperative Oncology Group (ECOG) performance status at 0-1 was the only independent predictor of longer OS (hazard ratio [HR] 0.13, 95% CI 0.02-0.801; p = 0.02), whereas a Karnofsky performance status (KPS) score <60 (HR 2.89, 95% CI 1.05-7.92; p = 0.03) and a cervical anatomical location (HR 4.14, 95% CI 1.32-12.98; p = 0.01) were independent predictors of shorter OS. The ambulatory status (Frankel D-E) (HR 0.38, 95% CI 0.07-1.985; p = 0.250) was not an independent prognostic factor, while the concomitant standard radiochemotherapy with temozolomide (Stupp protocol) (HR 0.35, 95% CI 0.118-1.05; p = 0.06) was at the limit of significance. DISCUSSION: Preoperative ECOG performance status, KPS score, and the location are independent predictors of OS of PsGBMs in adults. Further analyses are required to capture the survival benefit of concomitant standard radiochemotherapy with temozolomide.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Pessoa de Meia-Idade , Adolescente , Temozolomida , Glioblastoma/tratamento farmacológico , Estudos Retrospectivos , Prognóstico , Quimiorradioterapia , Neoplasias Encefálicas/patologiaRESUMO
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
Assuntos
Diferenciação Celular , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Diferenciação Celular/genética , Linhagem da Célula , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/patologia , Subunidades alfa de Fatores de Ligação ao Core/genética , Proteínas Hedgehog/metabolismo , Histona Desmetilases , Humanos , Antígeno Ki-67/metabolismo , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Metencéfalo/embriologia , Metencéfalo/patologia , Proteínas Musculares , Mutação , Fatores de Transcrição Otx/deficiência , Fatores de Transcrição Otx/genética , Proteínas Repressoras , Proteínas com Domínio T/metabolismo , Fatores de TranscriçãoRESUMO
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glândula Pineal , Pinealoma/genética , Pinealoma/patologia , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , MicroRNAs/metabolismo , Mutação/genética , Pinealoma/mortalidade , Sistema de Registros , Taxa de Sobrevida , Adulto JovemRESUMO
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
Assuntos
Neoplasias Cerebelares/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , RNA Nuclear Pequeno/genética , Adolescente , Adulto , Processamento Alternativo , Proteínas Hedgehog/metabolismo , Humanos , Mutação , Sítios de Splice de RNA , Splicing de RNARESUMO
BACKGROUND: After infant deaths due to non-accidental head injury (NAHI) with subdural hematoma (SDH), the magistrates ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of NAHI. We aimed to develop an SDH dating system applicable to infants aged under 3 years. METHODS AND RESULTS: We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SDH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12 histomorphological criteria relating to the clot and 14 relating to the dura mater in 73 victims (31 girls, 42 boys) whose median age was 3.8 months. Histopathological changes were significantly correlated with PTI for the appearance of red blood cells (RBCs) and the presence or absence of siderophages, and regarding the dura mater, the quantity of lymphocytes, macrophages, and siderophages; presence or absence of hematoidin deposits; collagen and fibroblast formation; neomembrane thickness; and presence or absence of neovascularization. Dating systems for SDH in adults are not applicable to infants. Notably, neomembrane of organized connective tissue is formed earlier in infants than in adults. CONCLUSION: Our dating system improves the precision and reliability of forensic pathological expert examination of NAHI, particularly for age estimation of SDH in infants. However, the expert can only define a time interval. Histopathology is indispensable to detect repetitive trauma.
Assuntos
Patologia Legal/métodos , Hematoma Subdural/patologia , Bilirrubina/metabolismo , Pré-Escolar , Colágeno/metabolismo , Dura-Máter/metabolismo , Dura-Máter/patologia , Eritrócitos/metabolismo , Feminino , Fibrina/metabolismo , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Trombose Intracraniana/metabolismo , Trombose Intracraniana/patologia , Linfócitos/metabolismo , Macrófagos/metabolismo , Masculino , Neovascularização Patológica , Mudanças Depois da Morte , Reticulina/metabolismo , Estudos RetrospectivosRESUMO
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
Assuntos
Meduloblastoma/classificação , Medicina de Precisão , Análise por Conglomerados , Estudos de Coortes , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Genômica , Humanos , Meduloblastoma/genética , Meduloblastoma/terapiaRESUMO
BACKGROUND: Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults. METHODS: We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type). RESULTS: The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3). CONCLUSION: In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto JovemRESUMO
The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1-84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH (mut)) (11.0 %), anaplastic astrocytoma IDH wild type (IDH (wt)) (5.3 %), glioblastoma IDH (mut) (17.1 %), and glioblastoma IDH (wt) (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p < 0.001). We did not find prognosis differences between grades III and IV for IDH (mut) 1p/19q intact and IDH (wt) gliomas in univariate and multivariate analyses. Among anaplastic astrocytoma IDH (wt), cases with chromosome arm 7p gain and 10q loss (55 %) had shorter PFS than the others (p = 0.027). In conclusion, the new WHO histomolecular classification of diffuse gliomas presented with high prognostic value. Grading was not discriminant between grade III and IV high-grade gliomas.
Assuntos
Astrocitoma/epidemiologia , Neoplasias Encefálicas/epidemiologia , Glioma/epidemiologia , Oligodendroglioma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/genética , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Glioma/classificação , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Oligodendroglioma/genética , Prognóstico , Organização Mundial da Saúde , Adulto JovemAssuntos
Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Índice Mitótico , Neovascularização Patológica , Oligodendroglioma/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Necrose , Oligodendroglioma/irrigação sanguínea , Oligodendroglioma/genética , Prognóstico , Taxa de SobrevidaRESUMO
Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Metilação de DNA , Genômica , Oligodendroglioma/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica/métodos , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Oligodendroglia/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/genética , Células-Tronco/metabolismo , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.
Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/cirurgia , Meduloblastoma/classificação , Meduloblastoma/cirurgia , Prognóstico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Canadá , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear. METHODS: Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries. RESULTS: We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively. CONCLUSION: ST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients.
Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Ependimoma/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Capilares/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Ependimoma/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Adulto JovemRESUMO
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Metilação de DNA , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/patologia , Sequência de Aminoácidos , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/diagnóstico , Criança , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Dados de Sequência Molecular , Tumores Neuroectodérmicos/classificação , Tumores Neuroectodérmicos/diagnóstico , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/química , Proteínas Repressoras/genética , Transdução de Sinais , Transativadores , Proteínas Supressoras de Tumor/genéticaRESUMO
Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression-free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glândula Pineal/metabolismo , Pinealoma/genética , Pinealoma/metabolismo , Adolescente , Adulto , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Neoplasias do Plexo Corióideo/classificação , Neoplasias do Plexo Corióideo/genética , Neoplasias do Plexo Corióideo/metabolismo , Neoplasias do Plexo Corióideo/patologia , Aberrações Cromossômicas , Metilação de DNA , Análise Mutacional de DNA , Intervalo Livre de Doença , Ependimoma/classificação , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Glândula Pineal/patologia , Pinealoma/classificação , Pinealoma/patologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismoRESUMO
Meningeal solitary fibrous tumors-hemangiopericytomas (SFT-HPC) and meningiomas can be difficult to distinguish on histologic examination. STAT6 immunohistochemistry (IHC) is a reliable diagnostic marker of SFT-HPCs. Recently, GRIA2 has also been reported to be a diagnostic marker of SFT-HPC, although no extensive data are available for meningeal SFT-HPCs yet. The aim of this study was to test their diagnostic performance in a large cohort of SFT-HPCs and meningiomas. IHC analyses for GRIA2 and STAT6 were performed on tissue microarrays containing 76 SFT-HPCs and 181 meningiomas. Results were compared with previous data with ALDH1 and CD34. Two different anti-STAT6 antibodies were tested: SC-20 polyclonal and YE361 monoclonal antibody. Ninety-six percent of meningeal SFT-HPCs but no meningioma displayed nuclear STAT6 positivity. With SC-20 antibody, concomitant cytoplasmic staining for STAT6 was observed in >50% of all cases, including meningiomas. However, using YE361 antibody, cytoplasmic staining was absent, and nuclear signal intensity was stronger leading to better interpretation of STAT6 IHC. GRIA2 was positive in 84% of SFT-HPCs and in 16% of meningiomas. STAT6 had excellent sensitivity (96%) and specificity (100%), ALDH1 and GRIA2 had same sensitivity (84%), but ALDH1 and CD34 had better specificity than GRIA2 (97% and 96% vs. 84%, respectively). For the differential diagnosis of SFT-HPCs versus meningiomas, the best diagnostic approach is to perform STAT6, followed by ALDH1 and CD34 in the case of uncommon STAT6-negative cases. Because of meningioma positivity, GRIA2 seems less useful in this indication.
Assuntos
Biomarcadores Tumorais/análise , Hemangiopericitoma/química , Imuno-Histoquímica , Neoplasias Meníngeas/química , Meningioma/química , Tumores Fibrosos Solitários/química , Família Aldeído Desidrogenase 1 , Antígenos CD34/análise , Biópsia , Hemangiopericitoma/patologia , Humanos , Isoenzimas/análise , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gradação de Tumores , Valor Preditivo dos Testes , Receptores de AMPA/análise , Retinal Desidrogenase/análise , Fator de Transcrição STAT6/análise , Tumores Fibrosos Solitários/patologia , Análise Serial de TecidosRESUMO
PURPOSES: The purpose of this study was to retrospectively study embryonal tumors with multilayered rosettes (ETMR), a rare new entity that gathers ETAN-TR (embryonal tumor with abundant neuropil and true rosettes), ependymoblastomas, and medulloepitheliomas, in order to improve their descriptions and try to better define therapeutic modalities. METHODS: Patients with ETMR, ETAN-TR, ependymoblastoma, and medulloepithelioma treated in SFCE centres (Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'adolescent) since 2000 were collected. Data were retrieved from clinical charts. RESULTS: Thirty-eight patients were included in the analysis. Seventeen had an ETAN-TR, 13 had a medulloepithelioma, and 8 had an ETMR. No ependymoblastoma was included. The median age at diagnosis was 31 months (range, 2.8-141 months). The predominant tumor location was supratentorial (66%); 18.4% patients had metastatic lesion. LIN28A expression was positive in 11/11 patients. Amplification of the locus 19q13.42 was positive in 10/12 patients. Thirty patients were treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol. The median time of follow-up was 0.9 years (range 0.1 to 15.3 years). The 1-year event-free survival (EFS) and overall survival (OS) were, respectively, 36% CI 95% (23-55) and 45% CI 95% (31-64). On multivariate analysis, complete surgical resection, radiotherapy, and high-dose chemotherapy were associated with a better overall survival with a relative risk of, respectively, 7.9 CI 95% (2.6-23.5) p < 0.0002, 41.8 CI 95% (9.4-186) p < 0.0001, and 3.5 CI 95% (1.3-9.5) p = 0.012. CONCLUSION: Prognosis of ETMR remains dismal despite multimodal therapy. LIN28A immunostaining and 19q13.42 amplification should be systematically done to secure the diagnosis. Complete surgical resection, radiotherapy, and high-dose chemotherapy are associated with better outcome.
Assuntos
Neoplasias Encefálicas/terapia , Quimioterapia Adjuvante , Tumores Neuroectodérmicos Primitivos/terapia , Procedimentos Neurocirúrgicos , Radioterapia Adjuvante , Neoplasias da Medula Espinal/terapia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Tumores Neuroectodérmicos Primitivos/patologia , Neurópilo/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias da Medula Espinal/patologiaAssuntos
DNA Helicases/análise , DNA Helicases/genética , Neoplasias Infratentoriais/genética , Mutação , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Tumor Rabdoide/genética , Teratoma/genética , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Pré-Escolar , Feminino , Humanos , Neoplasias Infratentoriais/diagnóstico , Tumor Rabdoide/diagnóstico , Teratoma/diagnósticoAssuntos
Neoplasias do Sistema Nervoso Central/patologia , Corpo Caloso/patologia , Linfoma/patologia , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Neoplasias do Sistema Nervoso Central/genética , Estudos de Coortes , Análise Mutacional de DNA , Genótipo , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Linfoma/genética , Imageamento por Ressonância MagnéticaRESUMO
Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO.